EP2289539A1 - Préparations d'insuline sans zinc ou pauvre en zinc dotées d'une stabilité améliorée - Google Patents

Préparations d'insuline sans zinc ou pauvre en zinc dotées d'une stabilité améliorée Download PDF

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Publication number
EP2289539A1
EP2289539A1 EP10178836A EP10178836A EP2289539A1 EP 2289539 A1 EP2289539 A1 EP 2289539A1 EP 10178836 A EP10178836 A EP 10178836A EP 10178836 A EP10178836 A EP 10178836A EP 2289539 A1 EP2289539 A1 EP 2289539A1
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EP
European Patent Office
Prior art keywords
insulin
pharmaceutical formulation
formulation according
human insulin
concentration
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP10178836A
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German (de)
English (en)
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EP2289539B1 (fr
Inventor
Peter Boderke
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Sanofi Aventis Deutschland GmbH
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Sanofi Aventis Deutschland GmbH
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Publication of EP2289539A1 publication Critical patent/EP2289539A1/fr
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Publication of EP2289539B1 publication Critical patent/EP2289539B1/fr
Priority to CY20121101060T priority Critical patent/CY1113318T1/el
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones

Definitions

  • the invention relates to stabilized pharmaceutical formulations containing a polypeptide selected from a group containing insulin (e.g., human insulin, bovine or porcine insulin), an insulin analog, an insulin derivative, active insulin metabolites or combinations thereof; a surfactant or combinations of several surfactants and optionally a preservative or combinations of several preservatives, and optionally an isotonizing agent, buffer or other adjuvants or combinations thereof, wherein the pharmaceutical formulation is low in zinc or zinc free.
  • insulin e.g., human insulin, bovine or porcine insulin
  • an insulin analog e.g., an insulin derivative, active insulin metabolites or combinations thereof
  • a surfactant or combinations of several surfactants and optionally a preservative or combinations of several preservatives e.g., a preservative or combinations of several preservatives
  • an isotonizing agent e.g., buffer or other adjuvants or combinations thereof
  • type II diabetes is not generally deficient in insulin, but in a large number of cases, especially in advanced stages, treatment with insulin, possibly in combination with an oral antidiabetic agent, is the most favorable form of therapy considered.
  • Diabetic late damage is microvascular and macrovascular damage, which may manifest as retinopathy, nephropathy, or neuropathy, leading to blindness, renal failure, and loss of extremities, in addition to an increased risk of cardiovascular disease. It can be deduced from this that an improved therapy of diabetes must primarily aim to keep the blood glucose as close as possible to the physiological range. According to the concept of intensified insulin therapy, this should be achieved by injections of fast-acting and slow-acting insulin preparations several times a day. Fast-acting formulations are given at meal times to compensate for the postprandial increase in blood glucose. Slow-acting basal insulins should ensure the basic supply of insulin, especially at night, without leading to hypoglycaemia.
  • Insulin is a 51 amino acid polypeptide distributed among 2 amino acid chains: the 21 amino acid A chain and the 30 amino acid B chain. The chains are linked by 2 disulfide bridges. Insulin preparations have been used for diabetes therapy for many years. Not only naturally occurring insulins are used, but more recently also insulin derivatives and analogues.
  • Insulin analogs are analogs of naturally occurring insulins, namely human insulin or animal insulins, which differ in substitution of at least one naturally occurring amino acid residue with other amino acid residues and / or addition / removal of at least one amino acid residue from the corresponding otherwise identical naturally occurring insulin.
  • the added and / or replaced amino acid residues may also be those that are not naturally occurring.
  • Insulin derivatives are derivatives of naturally occurring insulin or an insulin analog obtained by chemical modification.
  • the chemical modification may e.g. in the addition of one or more particular chemical groups to one or more amino acids.
  • insulin derivatives and insulin analogues have a slightly altered effect on human insulin.
  • Insulin analogues with accelerated onset of action are EP 0 214 826 .
  • EP 0 124 826 refers inter alia to substitutions of B27 and B28.
  • EP 0 678 522 describes insulin analogs that have different amino acids in position B29, preferably proline, but not glutamic acid.
  • EP 0 375 437 includes insulin analogues with lysine or arginine in B28, which may optionally be additionally modified in B3 and / or A21.
  • EP 0 419 504 discloses insulin analogs protected against chemical modifications in which asparagine in B3 and at least one other amino acid in positions A5, A15, A18 or A21 are altered.
  • Insulin analogs are described in which at least one amino acid of positions B1-B6 is replaced by lysine or arginine. Such insulins have according to WO 92/00321 a prolonged effect on.
  • the insulin preparations on the market of naturally occurring insulin for insulin substitution differ in the source of insulin (e.g., beef, pork, human insulin) and the composition with which the profile of action (onset and duration of action) can be affected.
  • the profile of action onset and duration of action
  • different profiles of action can be achieved and, if possible, adjusted to physiological blood sugar levels.
  • formulations of insulin derivatives or insulin analogues have been on the market showing altered kinetics.
  • Recombinant DNA technology nowadays enables the production of such modified insulins.
  • monomeric insulin analogues such as insulin lispro, insulin aspart and HMR 1964 (Lys (B3), glu (B29) human insulin) with a rapid onset of action, as well as insulin glargine with a prolonged duration of action.
  • Stabilized insulin formulations with increased long-term physical stability are needed in particular for preparations which are exposed to particular mechanical stresses or higher temperatures. These include, for example, insulins in application systems such as pens, inhalation systems, needleless injection systems or insulin pumps. Insulin pumps are either worn or implanted on the patient's body. In both cases, the preparation of the body heat and movement and the conveying movement of the pump and thus a very high thermo-mechanical load is exposed. Since insulin pens (disposable or reusable pens) are usually worn on the body, the same applies here. Previous preparations have only a limited stability under these conditions.
  • Insulin is in neutral solution in pharmaceutical concentration in the form of stabilized zinc-containing hexamers, which are composed of 3 identical dimer units ( Brange et al., Diabetes Care 13: 923-954 (1990 )).
  • the association of insulin can be reduced.
  • the insulin analogue lispro is present predominantly as a monomer and is thus absorbed more quickly and shows a shorter duration of action ( HPT Ammon and C. Werning; antidiabetics; 2nd ed.; Wiss. Verl.-Ges. Stuttgart; 2000; P. 94.f ).
  • the fast-acting insulin analogues which are present in monomer or dimer form, show a reduced stability and increased tendency to aggregate in the case of thermal and mechanical stress. It often manifests itself in turbidity and precipitation of insoluble aggregates.
  • These higher molecular weight transformation products (dimers, trimers, polymers) and aggregates not only reduce the dose of insulin administered but can also cause irritation or immune reactions in the patient.
  • insoluble aggregates can clog and clog the cannulas and hoses of the pumps. Since zinc leads to additional stabilization of insulin, zinc-free or low-zinc formulations of insulin and insulin analogues are particularly susceptible to instability.
  • the present invention was therefore based on the object to find zinc-free preparations for insulins and their derivatives and analogues, which are characterized by a high stability.
  • Insulin forms complexes in neutral preparations with zinc ions. With sufficient zinc concentration, 6 insulin molecules and 2 zinc ions form stable hexamers. To form this structure, a zinc concentration of at least 0.4% (w / w) based on the insulin is required. This corresponds with a preparation of 100 IU / ml insulin to a concentration of about 13 ⁇ g / ml zinc. An excess of zinc (eg 4 zinc ions per hexamer) stabilizes the preparation again significantly compared to physical stress ( J. Brange et al., Neutral insulin solutions stabilized by the addition of Zn2 +. Diabetic Med. 3, 532-536 (1986 )).
  • zinc-free or “zinc-poor” therefore means the presence of less than 0.4% by weight of zinc, based on the insulin content of the preparation, preferably less than 0.2% by weight, based on the insulin content.
  • the absence of zinc can also be achieved by adding zinc-complexing substances, such as citrate or EDTA, so that insufficient zinc ions are available to form the insulin / zinc hexamer complex.
  • the pharmaceutical preparations contain 60-6000 nmol / ml, preferably 240-3000 nmol / ml of an insulin, an insulin metabolite, an insulin analog or an insulin derivative.
  • the preparation may further contain preservatives (eg phenol, cresol, parabens), isotonizing agents (eg mannitol, sorbitol, lactose, dextrose, Trehalose, sodium chloride, glycerol) buffer substances, salts, acids and bases and other excipients. These substances may be present individually or as mixtures.
  • preservatives eg phenol, cresol, parabens
  • isotonizing agents eg mannitol, sorbitol, lactose, dextrose, Trehalose, sodium chloride, glycerol
  • Glycerol, dextrose, lactose, sorbitol and mannitol are usually present in the pharmaceutical preparation at a concentration of 100-250 mM, NaCl at a concentration up to 150 mM.
  • Buffer substances such as, for example, phosphate, acetate, citrate, arginine, glycylglycine or TRIS (ie 2-amino-2-hydroxymethyl-1,3-propanediol) buffer and corresponding salts, are in a concentration of 5-250 mM, preferably 10 - 100 mM available.
  • Other adjuvants statements may be salts, arginine, protamine, or surfing ®.
  • the invention therefore relates to a pharmaceutical formulation
  • a pharmaceutical formulation comprising a polypeptide selected from a group comprising insulin, an insulin analog, an insulin derivative, an active insulin metabolite or combinations thereof; a surfactant or combinations of several surfactants; optionally a preservative or combinations of several preservatives; and optionally an isotonizing agent, buffering agents and / or other adjuvants or combinations thereof, wherein the pharmaceutical formulation is free of or low in zinc; preferred is such a pharmaceutical formulation, wherein the surfactant is selected from a group containing alkali, amine, alkaline earth metal soaps, alkyl sulfates, alkyl sulfonates, natural surfactants, cationic surfactants, fatty alcohols, partial and fatty acid esters of polyhydric alcohols such as glycerol and sorbitol, polyols; wherein said soaps are selected from a group containing stearates, palmitates, oleates,
  • the invention further provides a pharmaceutical formulation as described above, in which the insulin, the insulin analog, the active insulin metabolite and / or the insulin derivative are present in a concentration of 60-6000 nmol / ml, preferably in a concentration of 240-3000 nmol / ml is present (this corresponds approximately to a concentration of 1.4-35 mg / ml or 40-500 units / ml); in which the surfactant is present in a concentration of 0.1 to 10,000 ⁇ g / ml, preferably in a concentration of 1 to 1000 ⁇ g / ml.
  • Another object of the invention is a pharmaceutical formulation as stated above, in which glycerol and / or mannitol in a concentration of 100-250 mM, and / or chloride is preferably present in a concentration up to 150 mM.
  • Another object of the invention is a pharmaceutical formulation as stated above, in which a buffer substance in a concentration of 5 - 250 mM is present.
  • Another object of the invention is a pharmaceutical insulin formulation containing other additives such as salts, protamine or surfing ® , which retard the release of insulin. Also included are mixtures of such sustained-release insulins with formulations described above.
  • Another object of the invention is a method for producing such pharmaceutical formulations.
  • another object of the invention is the use of such formulations for the treatment of diabetes mellitus.
  • Another object of the invention is the use or addition of surfactants as a stabilizer during the manufacturing process of insulin, insulin analogues or insulin derivatives or their preparations.
  • the pH is between 2 and 12, preferably between 6 and 8.5, and more preferably between 7 and 7,8.
  • polysorbate 20 delays the occurrence of turbidity very clearly.
  • Poloxamer 171 significantly delays the occurrence of turbidity and stabilizes the preparation.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Endocrinology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Immunology (AREA)
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  • Emergency Medicine (AREA)
  • Dermatology (AREA)
  • Biochemistry (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP10178836A 2001-03-23 2002-03-09 Préparations d'insuline sans zinc ou pauvre en zinc dotées d'une stabilité améliorée Expired - Lifetime EP2289539B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CY20121101060T CY1113318T1 (el) 2001-03-23 2012-11-08 Ελευθερα απο ψευδαργυρο και φτωχα σε ψευδαργυρο σκευασματα ινσουλινης με βελτιωμενη σταθεροτητα

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10114178A DE10114178A1 (de) 2001-03-23 2001-03-23 Zinkfreie und zinkarme Insulinzubereitungen mit verbesserter Stabilität
EP02729985A EP1381385B1 (fr) 2001-03-23 2002-03-09 Preparations d'insuline a stabilite amelioree, exemptes de zinc ou a faible teneur en zinc

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
EP02729985.8 Division 2002-03-09
EP02729985A Division EP1381385B1 (fr) 2001-03-23 2002-03-09 Preparations d'insuline a stabilite amelioree, exemptes de zinc ou a faible teneur en zinc

Publications (2)

Publication Number Publication Date
EP2289539A1 true EP2289539A1 (fr) 2011-03-02
EP2289539B1 EP2289539B1 (fr) 2012-09-19

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ID=7678654

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Application Number Title Priority Date Filing Date
EP02729985A Expired - Lifetime EP1381385B1 (fr) 2001-03-23 2002-03-09 Preparations d'insuline a stabilite amelioree, exemptes de zinc ou a faible teneur en zinc
EP10178836A Expired - Lifetime EP2289539B1 (fr) 2001-03-23 2002-03-09 Préparations d'insuline sans zinc ou pauvre en zinc dotées d'une stabilité améliorée

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EP02729985A Expired - Lifetime EP1381385B1 (fr) 2001-03-23 2002-03-09 Preparations d'insuline a stabilite amelioree, exemptes de zinc ou a faible teneur en zinc

Country Status (32)

Country Link
US (5) US6960561B2 (fr)
EP (2) EP1381385B1 (fr)
JP (1) JP4231292B2 (fr)
KR (2) KR20100061868A (fr)
CN (1) CN1273187C (fr)
AR (2) AR033059A1 (fr)
AT (1) ATE497777T1 (fr)
AU (1) AU2002302409B2 (fr)
BR (1) BRPI0208210B8 (fr)
CA (1) CA2441260C (fr)
CY (2) CY1111413T1 (fr)
DE (2) DE10114178A1 (fr)
DK (2) DK1381385T3 (fr)
ES (2) ES2393180T3 (fr)
HK (1) HK1061521A1 (fr)
HR (1) HRP20030765B1 (fr)
HU (1) HU228847B1 (fr)
IL (2) IL158057A0 (fr)
ME (1) ME00408B (fr)
MX (1) MXPA03007942A (fr)
MY (1) MY129417A (fr)
NO (1) NO326780B1 (fr)
NZ (1) NZ528335A (fr)
PE (1) PE20020968A1 (fr)
PL (1) PL205465B1 (fr)
PT (2) PT1381385E (fr)
RS (1) RS51579B (fr)
RU (1) RU2311922C2 (fr)
SI (1) SI1381385T1 (fr)
TW (1) TWI301761B (fr)
WO (1) WO2002076495A1 (fr)
ZA (1) ZA200306637B (fr)

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AR033059A1 (es) 2003-12-03
PL205465B1 (pl) 2010-04-30
DE50214903D1 (de) 2011-03-24
BRPI0208210B8 (pt) 2021-05-25
CN1498113A (zh) 2004-05-19
RU2311922C2 (ru) 2007-12-10
HRP20030765A2 (en) 2005-06-30
US6960561B2 (en) 2005-11-01
HK1061521A1 (en) 2004-09-24
TWI301761B (en) 2008-10-11
SI1381385T1 (sl) 2011-05-31
EP1381385A1 (fr) 2004-01-21
PT2289539E (pt) 2012-11-20
AR096376A2 (es) 2015-12-23
NZ528335A (en) 2005-03-24
US7205277B2 (en) 2007-04-17
NO326780B1 (no) 2009-02-16
US7452860B2 (en) 2008-11-18
IL158057A0 (en) 2004-03-28
YU73503A (sh) 2006-05-25
BR0208210A (pt) 2004-03-09
PL362800A1 (en) 2004-11-02
US7205276B2 (en) 2007-04-17
BRPI0208210B1 (pt) 2018-05-02
MY129417A (en) 2007-03-30
ES2393180T3 (es) 2012-12-19
KR100987311B1 (ko) 2010-10-13
DK1381385T3 (da) 2011-06-06
US20050187142A1 (en) 2005-08-25
US20030004096A1 (en) 2003-01-02
KR20040011483A (ko) 2004-02-05
ZA200306637B (en) 2004-05-07
MXPA03007942A (es) 2004-04-02
PE20020968A1 (es) 2002-12-10

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